INCRETINAS: NUEVAS ESTRATEGIAS CONTRA LA DMT2

Presentación del tema: "INCRETINAS: NUEVAS ESTRATEGIAS CONTRA LA DMT2"— Transcripción de la presentación:

1 INCRETINAS: NUEVAS ESTRATEGIAS CONTRA LA DMT2
Zaragoza, 16 de abril del 2012 Acisclo Pérez Martos

2 RESUMEN INTRODUCCION A LA DMT2 Y COMPLICACIONES DIVERSAS PATOGENESIS , FISIOPATOLOGIA TRATAMIENTO ACTUAL DE LA DMT2 Y PROBLEMAS A RESOLVER HORMONAS QUE CONTROLAN LA GLUCEMIA INCRETINAS: PERSPECTIVAS HISTORICAS INCRETINAS COMO COMPONENTES DE LA FAMILIA DEL GLUCAGON SECRECIÓN DE INSULINA POR GLUCOSA Y POR INCRETINAS FUNCIONES DE LAS INCRETINAS (CARDIOVASCULARES) DPP-4 TERAPIA BASADA EN INCRETINAS

3 ¿QUE ES LA DIABETES MELLITUS TIPO 2?
Enfermedad metabólica progresiva con hiperglucemia, como consecuencia de una combinación de resistencia a la insulina y a una inadecuada respuesta secretora de insulina (OMS calcula 340 millones de diabéticos. Mas del 60% muere por complicaciones cardiovasculares) En la DMT2 están implicados dos procesos patológicos Deterioro progresivo de las función de los islotes pancreáticos Disminución de la respuesta de los tejidos a la insulina (resistencia a la insulina)

4 COMPLICACIONES DE LA DMT2
Alta incidencia macrovascular Complicaciones microvasculares

5 1% Incidencia de complicaciones clínicas asociadas con la glucemia
(PSG = Proteínas Séricas Glucosiladas) Valores máximos de 6-7% mas del 60% tiene valores mas elevados Complicaciones microvasculares (nefropatía, ceguera)* Amputación o afección severa de vasos periféricos * Ictus** Muertes relacionadas con DM* 21% 37% 12% 43% IAM* 14% * p<0.0001 ** p=0.035 1% HbA1c Stratton IM et al. BMJ 2000;321: 405 – 412

6 Patogénesis de Diabetes Mellitus tipo 2

7 Resistencia a la insulina (menor captación de glucosa)
Fisiopatología de la Diabetes Mellitus tipo 2 Islote Déficit de insulina Páncreas célula alfa produce exceso de glucagón célula beta produce menos insulina Exceso de glucagón Menos insulina Hígado Músculo y grasa Hiperglucemia Producción excesiva de glucosa Resistencia a la insulina (menor captación de glucosa) Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; Rhodes CJ Science 2005;307:380–384.

8 Secreción inapropiada
TERAPIAS ACTUALES CONTRA LA DMT2 Elevar los niveles de insulina: Administración directa de insulina Agentes orales que favorecen la secreción Mejorar la sensibilidad de los tejidos por la insulina Reducir la absorción de carbohidratos en el tracto intestinal Reducción la liberación de glucosa hepática Hiperglucemia Absorción de HC Aumento producción hepática de glucosa Secreción inapropiada de insulina Metformina Glitazonas Biguanidina Glitazonas Metformina Inh. -glucosidasas Sulfonilureas Meglitinidas Insulina Descenso captación Muscular glucosa

9 PROBLEMAS SIN RESOLVER QUE ACTUALMENTE ESTAN EN INVESTIGACIÓN
(potenciales dianas para futuras terapias) 1.- Sensibilidad reducida de las células b por la glucosa (Sensor de glucosa) 2.- Pérdida de función y número de las células b (progreso de la enfermedad) 3.- Pérdida de secreción de insulina 4.- Pérdida de respuesta a la insulina a las oscilaciones de la concentración de glucosa 5.- Ratio elevada de Proinsulina / Insulina 6.- Secreción aumentada de Glucagón (aumento de glucosa) 7.- Secreción anormal de amilina (reduce la concentración de glucosa postprandial) 8.- Enlentecimiento del vaciado gástrico (facilita de reducción de la ingesta y peso corporal) 9.- Reabsorción renal de glucosa (SGLT2) (Mas del 40% de glucemia procede del riñón) Algunos de estos problemas se intentan resolver con la terapia de incretinas

10 Necesidades de la glucosa
160 g de glucosa diarios 120 g para el cerebro 40 g para el resto del organismo Disponibilidad de glucosa En líquidos corporales g de glucosa Procedente del glucógeno 190 g de glucosa SOLAMENTE HAY RESERVAS GLUCÍDICAS PARA UN DIA

11 Insulina y glucagón regulan la homeostasis de la glucosa
¿¿¿¿¿¿

12 Dinámica de insulina y glucagón en respuesta al alimento en sujetos normales y diabéticos tipo 2
-60 60 120 180 240 20.0 18.3 16.6 15.0 13.3 6.1 4.4 140 130 110 100 90 30 Glucose (mmol/l) Insulin (mU/l) Glucagon (ng/l) Meal Time (min) Type 2 diabetes Normal subjects Delayed/depressed insulin response Nonsuppressed glucagon Insulin and glucagon dynamics in response to meals in normal subjects and Type 2 diabetes This slide illustrates a study that measured plasma glucose, insulin, and glucagon response in individuals without (normal subjects) and with Type 2 diabetes. The study was conducted after an overnight fast followed by a high-carbohydrate meal. Plasma glucose concentrations rose from 12.7 mmol/l (228 mg/dl), pre-meal, to 19.9 mmol/l (358 mg/dl) in individuals with Type 2 diabetes compared with an increase from 4.7 mmol/l (84 mg/dl) to a peak of 7.6 mmol/l (137 mg/dl) in normal subjects. Insulin levels rose in normal individuals from a fasting level of 13 mU/l to a peak of 136 mU/l at 45 minutes. The insulin response in individuals with Type 2 diabetes was depressed, with a modest increase from a fasting level of 21 mU/l to a peak of 50 mU/l at 60 minutes. In normal individuals, plasma glucagon began to fall from the fasting value of 126 ng/l (126 pg/ml) within 30 minutes of the start of the meal and reached a significantly lower concentration of 90 ng/l (90 pg/ml) at 90 minutes (P<0.01). Plasma glucagon concentrations in those with Type 2 diabetes did not fall in response to the meal, despite the sharp increase in plasma glucose. These results demonstrate the delayed and suppressed insulin response to rising plasma glucose concentrations in individuals with Type 2 diabetes. Importantly, it also shows the lack of postprandial suppression of glucagon in Type 2 diabetes following a meal; this stands in marked contrast to the rapid fall in glucagon levels among normal subjects. The combined effect of decreased insulin secretion and glucagon over-secretion in Type 2 diabetes leads to fasting hyperglycaemia and increases postprandial hyperglycaemia. REFERENCE Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. N Engl J Med. 1970;283: Normal subects n=11; Type 2 diabetes n=12 Müller et al. N Engl J Med. 1970

13

14

15 INtestinal seCRETion of INsulin
Sustancias derivadas de los intestinos, que se liberan tras la ingestión oral de nutrientes y aumentan la liberación de insulina

16

17 PERSPECTIVAS HISTÓRICAS
8% PERSPECTIVAS HISTÓRICAS Demostración del GIP es una incretina. En humanos el GIP (Peptido Inhibidor Gastrico) se cambia a Peptido Insulinotropico dependiente de Glucosa Definición efecto incretina Actividad hormonal del intestino que aumenta la secreción pancreática La encima DPP-4 degrada GIP y GLP-1 Llevó al desarrollo de fármacos contra la DMT2 1902 1932 1964 1973 1987 1995 2000 1ª Observación efecto incretina Un factor intestinal estimula secreción pancreática Demostración del efecto de las incretinas. La glucosa por vía oral produce mas efecto que por vía IV Demostración que GLP-1 es una incretina humana En humanos se demuestra una 2ª hormona intestinal análoga al Glucagon Investigación en curso de: Inhibidores de DPP-4 Simuladores de incretinas

18 Pertenecen a una superfamilia de péptidos del Glucagón por lo
que tienen homología en su secuencia de aminoácidos (21 y 48%) (Intestino, Páncreas, S. Nervioso. Gran variedad de funciones) GLUCAGON SECRETINA VIP GIP PHI PHM GHRH GLICENTINA GLP-1 (7-37) GLP-1 (7-36)AMIDA GLP-2 OXINTOMODULINA PACAP (Péptido activador de adenilato ciclasa) (de ovino) PEPTIDOS AISLADOS DE VENENO DE LAGARTOS (Monstruo de Gila) HELODERMINA HELOSPECTINA I HELOSPECTINA II EXENDINA 3 EXENDINA 4 (53% homologia con GLP-1, agonista) EXENDINA (9-39) (Antagonista)

19 Expresión del gen pre-proglucagon: 6 Exones (E1 – E6)
5 Intrones (IA – IE) No splicing alternativo M = Metionina Inicio Traducción UN-TX = No traducida Procesamiento posttraduccional por enzimas Prohormona Convertasas (PC) Diferencias de procesamiento Numerosas hormonas peptídicas multifuncionales implicadas en el metabolismo de nutrientes

20 Las incretinas GLP-1: Glucagón-Like Peptide 1 45% de homología
F S V S L G A H E T T D S Y E Q A 45% de homología A K R K L F G V W I E G GIP: Gastric Inhibitory Polypeptide Glucose-Dependent Insulinotropic Polypeptide A G F S Y I M K H Y E T I D S A D I Major discussion point: There have been 2 important incretins identified thus far: GLP-1 (glucagon-like peptide 1) and GIP (originally “gastric inhibitory polypeptide,” but it was later determined that GIP did not inhibit gastric function and the name was changed to “glucose-dependent insulinotropic polypeptide,” retaining the GIP acronym). Both of these peptides share amino acid sequences similar to those found in glucagon. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: Q Q D K G A N N K L F V W K Q L W D K T N I Q H 35% homología Amino acids shown in are homologous with the structure of glucagon. MORADO Drucker. Diabetes Care. 2003;26:2929

21 La glucosa estimula la secreción de insulina
Ca2+ Glucosa Canal de Ca2+ voltaje-dependiente Canal de K/ATP DISCUSSION The basic glucose-stimulated insulin secretion pathway involves the following steps: Glucose enters the cell through the glucose transporter Glucose metabolism causes a rise in intracellular ATP and a decrease in intracellular ADP, resulting in an increase in the ATP/ADP ratio This increase in the ATP/ADP ratio causes the ATP sensitive K channels to close, causing a depolarisation of the plasma membrane The depolarisation activates voltage-dependent Ca2+ channels, allowing influx of Ca2+ The increased Ca2+ stimulates the exocytosis of insulin granules Abbreviations ADP = adenosine diphosphate ATP = adenosine triphosphate Ca2+ = calcium cAMP = cyclic adenosine monophosphate K = potassium ↑ATP/ADP Liberación de insulina Transportador de glucosa Gránulos de insulina Receptor de GLP-1 Célula β Pancreática Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435: ; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

22 Transportador de glucosa Liberación de insulina
Se libera una cantidad limitada de insulina en respuesta a la estimulación del receptor de GLP-1 ante la ausencia de glucosa Glucosa Canal de K/ATP Canal de Ca2+ voltaje-dependiente DISCUSSION In the absence of glucose, GLP-1 signaling has little effect on insulin secretion. The GLP-1 receptor is a G-protein coupled receptor that works through a cAMP-dependent pathway to increase intracellular Ca2+. Abbreviations ADP = adenosine diphosphate ATP = adenosine triphosphate cAMP = cyclic adenosine monophosphate Ca2+ = calcium K = potassium Ca2+ cAMP ATP Transportador de glucosa Liberación de insulina Gránulos de insulina Receptor de GLP-1 Célula β Pancreática

23 Transportador de glucosa Liberación de insulina
Las acciones insulinotrópicas de GLP-1 son glucodependientes Ca2+ Glucosa Canal de Ca2+ voltaje-dependiente Canal de K/ATP DISCUSSION The combination of GLP-1 activity and glucose-stimulated insulin secretion results in increased insulin secretion. The presence of the GLP-1-activated pathway delays the repolarisation of the membrane, allowing a longer period of Ca2+ influx. The increased concentration of intracellular Ca2+ results in even greater insulin release. Abbreviations ADP = adenosine diphosphate ATP = adenosine triphosphate Ca2+ = calcium cAMP = cyclic adenosine monophosphate K = potassium ↑ATP/ADP Ca2+ cAMP ATP Transportador de glucosa Liberación de insulina Gránulos de insulina Receptor de GLP-1 Célula β Pancreática Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435: ; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

24 GLUT2 Km = 15 mM GLUT3 Km = 1 mM GK Km = 10mM En cerebro
Cell Metabolism – January 2006

25 15 mM Glucosa, aumenta la actividad (compite con F-6-P)
F-6-P disminuye la actividad F-1-P aumenta la actividad ¿diabéticos? (4-5 mM) Km = 15 mM F-1-P 15 mM

26 Endocrine Reviews 20(6): 876–913 1999
FIG. 14. Insulinotropic actions of GLP-1 on 􏰁-cells mediated by ac- tivation of the cAMP-signaling pathway. The binding of GLP-1 to its receptor (Re) activates adenylyl cyclase (Ac), resulting in the forma- tion of cAMP. Binding of cAMP to the regulatory (R) subunit of PKA results in the release of the active catalytic (C) subunit. The active kinase then translocates to the nucleus and phosphorylates, and therefore activates, the nuclear transcriptional activator CREB bound to the CRE located in the promoter of the proinsulin gene. This cascade of signaling results in a stimulation of transcription of the proinsulin gene and increased insulin biosynthesis to replete stores of insulin secreted in response to nutrients (glucose) and incretins (GLP-1, GIP). [Adapted with permission from J. F. Habener: In Di- abetes Mellitus, pp 68-78, 1996 (588)]. Endocrine Reviews 20(6): 876–

27 Binding of GLP-1 to its receptor in b-cells results in an increase in intracellular cAMP, leading to the stimulation of insulin exocytosis by two different pathways: PKA-dependent and PKA-independent (EPAC) [29]. GLP-1 also increases the activity of PDX1, leading to the regulation of gene expression. The anti-apoptotic effect of GLP-1 is mediated by the activation of CREB via the phosphorylation by PKA and its interaction with a coactivator named TORC2. To migrate into the nucleus, TORC2 is dephosphorylated via the synergistic activation of TORC2 phosphatase and inhibition of TORC2 kinase, mediated by calcium and cAMP, respectively [61]. Activated CREB enhances gene expression (e.g. IRS-2, which is involved in the activation of PKB) [44]. GLP-1 also activates the PI3K pathway by two distinct mechanisms: GLP-1 receptor activation of the Gs protein whereby the subunit dimer interacts with PI3K; and activation of c-Src followed by the liberation of an endogenous epidermal growth factor (EGF)-like ligand, b-celluline, which in turn activates the EGF receptor and increases PI3K activity [46]. PI3K subsequently activates its downstream targets MAPK, ERK, PKCz and PKB/Akt. In b-cells, PKC and MAPK activation are associated with GLP-1-induced proliferation, whereas ERK and MAPK activation leads to b-cell differentiation. Stimulation of PKB protects b-cells against apoptosis. AC, adenylyl cyclase; CREB, cAMP response element binding protein; EGF-R: epidermal growth factor receptor; GK: glucokinase enzyme; GLUT2, glucose transporter-2; Ins, insulin; IRS-2, insulin-receptor substrate-2; TORC2, transducer of regulated CREB activity.

28 The Journal of Clinical Investigation Vol 117 January2007

29 Endocrine Reviews, April 2012, 33(2):187–215
GLP-1 targets multiple organs to improve glucose control in T2DM. GLP-1 acts directly and indirectly on several peripheral tissues that contribute to lowering of blood glucose levels. These include potent effects on the pancreatic 􏰊-cell to stimulate insulin secretion, inhibition of 􏰉-cell glucagon secretion that reduces hepatic glucose production, a decrease in gastric motility, and a reduction in appetite that contributes to weight loss, reduced levels of adipocytokines, and decreased inflammation. GLP-1 targets multiple organs to improve glucose control in T2DM. GLP-1 acts directly and indirectly on several peripheral tissues that contribute to lowering of blood glucose levels. These include potent effects on the pancreatic bcell to stimulate insulin secretion, inhibition of a-cell glucagon secretion that reduces hepatic glucose production, a decrease in gastric motility, and a reduction in appetite that contributes to weight loss, reduced levels of adipocytokines, and decreased inflammation. Endocrine Reviews, April 2012, 33(2):187–215

30 Endocrine Reviews, April 2012, 33(2):187–215
Antiatherosclerotic potential of GLP-1 action. The direct actions of GLP-1 on blood vessels and macrophages and on the regulation of plasma lipid profiles may impact the development and/or progression of atherosclerotic plaques. Antiatherosclerotic potential of GLP-1 action. The direct actions of GLP-1 on blood vessels and macrophages and on the regulation of plasma lipid profiles may impact the development and/or progression of atherosclerotic plaques. Endocrine Reviews, April 2012, 33(2):187–215

31 Impact of GIP/GLP-1 on islet hormone release
Impact of GIP/GLP-1 on islet hormone release. Nutrient ingestion triggers insulin release from islet b-cells via several mechanisms comprising the enteroinsular axis. (i) The intestinal incretin hormones GIP and GLP-1 are released from secretory granules in enteroendocrine cells (shown in green) and function as endocrine mediators of insulin secretion. Nutrient absorption from the gut lumen can directly activate insulin release via the bloodstream, and (ii) the presence of nutrients in the gut can also activate neural pathways (shown in yellow) that influence the secretion of islet hormones. Finally, in addition to enteroinsular mechanisms, release of (iii) islet GLP-1 and GIP might influence the growth, survival and function of islet cells (shown in red) through local paracrine and/or autocrine actions. The dashed arrow indicates ambiguity in this process.

32 GLP-1 integrates energy metabolism, feeding behavior and learning
GLP-1 integrates energy metabolism, feeding behavior and learning.GLP-1 is produced by L-cells in the intestine and is released from those cells into the blood in response to food ingestion. GLP-1 binds to receptors (R) on pancreatic -cells, resulting in the activation of a GTP-binding protein (g) and adenylate cyclase (AC), thereby stimulating cyclic AMP production and calcium influx. Cyclic AMP and calcium stimulate rapid release of insulin from the cells and induce transcription of the insulin gene, thereby replenishing insulin stores. Insulin enhances glucose uptake by muscle cells; GLP-1 therefore has an antidiabetic action. GLP-1 also activates receptors in neurons located in the hypothalamus, resulting in a reduction in food intake; thus, GLP-1 has an important role in controlling energy balance. GLP-1 receptors are also located on neurons in brain regions, such as the hippocampus, that are involved in learning and memory. During et al. report that GLP-1 indeed enhances learning and memory. The exact mechanism is unknown, but GLP-1 might act on presynaptic axon terminals to enhance the release of glutamate, much like it stimulates insulin release from -cells. Alternatively, GLP-1 may bind to postsynaptic receptors in dendrites, resulting in activation of the cyclic AMP− and calcium-responsive protein CREB, a transcription factor known to have an important role in learning and memory. Nature Medicine  9, (2003)

33

34 Familia de terapia basada en incretina
Análogo de GLP-1 humano, por ej. liraglutida Terapias a base de exendina, por ej. exenatida agonista receptor de GLP-1 inhibidores DPP-4, por ej. sitagliptina, vildagliptina incretina Familia de terapias a base de incretina Las terapias a base de incretina puede dividirse ampliamente entre: Inhibidores DPP-4 (por ej. sitagliptina, vildagliptina) agonista receptor de GLP-1 (Exenatida, liraglutida) Con esta segunda categoría sin embargo, los agonistas de GLP-1R pueden ser clasificados como: Terapias a base de exendina (exenatida, exenatida LAR) cuya secuencia es idéntica en ~50% con el GLP-1 humano Análogos de GLP-1 humano (liraglutida), con un porcentaje muy superior de similitud con GLP-1 humano (97%) Byetta® Lilly (Victoza® Novo) 34

35 Structural similarities and differences between GLP-1, exenatide, liraglutide and CJC-1134-PC
Versión sintética de exendine-4 ( en 2012 una semanal) 97% analogía secuencia Se libera lentamente de la albumina (t1/2 = 11-15h) No induce hipoglucemia (dependiente conc. Glucosa) Proteína hibrida recombinante. Vida media mas larga

36 Endocrine Reviews, April 2012, 33(2):187–215
SDF-1 = Citoquina activadora de Linfocitos BNP (1-32) = Péptido implicado en presión sanguínea NPY (3-36) = Neuropeptido PYY (1-36) = Péptido liberado de Ileon y Colon. Reduce el apetito Endocrine Reviews, April 2012, 33(2):187–215

37 Endocrine Reviews, April 2012, 33(2):187–215

38 Endocrine Reviews, April 2012, 33(2):187–215

39

40 El guardian del genoma dice……..
¡¡¡¡Ave….mus acabadus!!!!